Urea foam

ABSTRACT

Provided, among other things, is a delivery module for a non-greasy, water-based urea composition comprising: an aerosol delivery device; within the aerosol delivery device, the urea composition comprising 20% or more urea by weight, non-greasy lipophilic component(s), and a frothing agent, the urea composition having a viscosity low enough to support aerosol delivery, and the urea composition effective to form a foam upon propellant-driven aerosol delivery; and within the aerosol delivery device, a propellant.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of and claims the benefit of priorityof pending U.S. patent application Ser. No. 12/016,371, filed on Jan.18, 2008, which claims priority to Provisional application Ser. No.60/885,677, filed Jan. 19, 2007, both of which are incorporated hereinby reference in their entirety.

TECHNICAL FIELD

The present invention relates to foam-forming composition of urea, whichcan be used to treat psoriasis, and thickened areas of the soles,elbows, knees and the like.

BACKGROUND

Urea, especially in high concentrations, can be used to treat dry scalyskin, or skin that has thickened to a non-cosmetic or uncomfortabledegree. This activity has been attributed to the ability of urea tosolubilize and denture protein. Urea can be used to treat xerosis,ichthyosis (e.g., ichthyosis vulgaris), psoriasis, atopic dermatitis,and the like. Such treatment can include itch relief, at least temporaryitch relief.

Dermatological compositions of concentrated urea have been formulated inoily bases. Such a oil-based formulations provide a protective layer andlocalize the urea on the skin. Despite the bias in the industry toformulate in oil-based ointments, Applicant sought to make awater-based, foam-forming composition.

In seeking to formulate a water-based, foam-forming composition, it wasdiscovered that high urea concentrations destabilize formulations thatare otherwise stable, water-based dermatological formulations, yieldingcompositions that form sediments to a degree that makes properdispensing difficult. Described herein are parameters within which onecan formulate stable, water-based compositions of urea at highconcentration.

SUMMARY

Provided, among other things, is a delivery module for a non-greasy,water-based urea composition comprising: an aerosol delivery device;within the aerosol delivery device, the urea composition comprising 20%or more urea by weight, non-greasy lipophilic component(s), and afrothing agent, the urea composition having a viscosity low enough tosupport aerosol delivery, and the urea composition effective to form afoam upon propellant-driven aerosol delivery; and within the aerosoldelivery device, a propellant.

Further provided, among other things, is a urea composition comprising:urea 20-50%; fatty acid(s) and/or analogous alkyl amine(s) 1-5%;hydrophilic polymer(s) 0.5-1.5%; titrant, as needed in amount effectiveto substantially neutralize the fatty acid(s) or alkyl amine(s);frothing agent 0.3-4%; and humectant 0.5-7%.

Also provided, among other things, is a method of treating dermatitis,psoriasis, xerosis, ichthyosis, eczema, keratosis, keratoderma, dry andrough skin, corns, calluses, damaged, or ingrown and devitalized nailscomprising applying to affected skin a foamed, non-greasy, water-basedurea composition comprising: 20% or more urea by weight, non-greasylipophilic component(s), and a frothing agent, the urea compositionhaving a viscosity low enough to support aerosol delivery, and the ureacomposition effective to form a foam upon propellant-driven aerosoldelivery.

DETAILED DESCRIPTION

Urea can be present, for example, in amounts from about 20% by weight toto about 50% by weight, or to about saturation (in the composition).Unless otherwise detailed, all amount percentages presented in thisspecification are weight percentages. In certain embodiments, urea is20% or more, 25% or more, 30% or more, 31% or more, or 32% or more, or33% or more, or 34% or more, or 35% or more, or 36% or more, or 37% ormore, or 38% or more, or 39% or more of the urea composition. In certainembodiments, urea is 49% or less, or 48% or less, or 47% or less, or 46%or less, or 45% or less, or 44% or less, or 43% or less, or 42% or less,or 41% or less of the urea composition.

It is believed that urea formulated in an aqueous solution canfacilitate urea absorption on skin. A non-greasy skin-feel, which can beachieved with the present formulation, allows for more frequentapplications than would be cosmetically acceptable with oil basedformulations.

The composition can contain lipophilic components that are believed tohelp distribute urea on and into the skin. A major portion of suchlipophilic components can be amphiphates in amounts effective tostabilize the lipophilic components in solution and/or emulsified.Example amphiphates are fatty acids, which can be substantially oressentially ionized, wherein the salt is soluble in the aqueous solutionof the urea composition. Further examples are alkyl amines with onealkyl per amine having a size distribution analogous to that of anappropriate fatty acid composition. Further examples are nonionicdetergents.

The fatty acid can, for example, be of any composition found in anatural source, including hydrolysis of esterified fatty acids. Or, thefatty acid component can be hydrogenated to remove substantially all ora portion of any unsaturation. In certain embodiments, the fatty acidcomponent or the alkyl moiety of the alkyl amine component is selectedsuch that 50 mole % or more is C12 or higher, or C14, or C16 or higher.In certain embodiments, the fatty acid component or the alkyl moiety ofthe alkyl amine component is selected such that 50 mole % or more is C22or lower, or C20 or lower, or C18 or lower. In certain embodiments, 75mole % or more of the fatty acid component is from C12 or C14 or C16 toC22 or C20 or C18. In certain embodiments, 80 mole % or more, 85 mole %or more, 90 mole % or more, 95 mole % or more, 97 mole % or more, 98mole % or more, or 99 mole % or more, meets one of the size parametersof this paragraph.

For carboxylic acid containing lipophilic components, useful saltsinclude the alkali metal salts such as sodium or potassium salts;ammonium salts; salts formed with suitable organic bases, such as aminesalts (such as triethyl amine, triethanol amine, or the like) andquaternary ammonium salts; or the like. Bivalent or trivalent salts canbe used where they do not adversely affect solubility. Foramine-containing lipophilic components, useful salts include maleates,fumarates, lactates, oxalates, methanesulfonates, ethanesulfonates,benzenesulfonates, tartrates, citrates, halides (e.g., hydrochlorides,hydrobromides), sulfates, phosphates, nitrates, and the like. As needed,the lipophilic components are provided such that a sufficient amount ofconstituent ionizable molecules are in ionized (salt) form to providesolubility. Such ionized forms can be prepared by adding a titrant,though recitations of compositions described by such titration includethe equivalent compositions formed by pre-formed salts or otherwise.

The lipophilic component may include 50% or less of a more hydrophobiccomponent, such as one that can be termed an emollient. This morehydrophobic component can be, for example, 45% or less, or 40% or less,or 35% or less, or 30% or less, or 25% or less, or 20% or less, of thelipophilic component.

In certain embodiments, the lipophilic component is 1% or more, or 1.5%or more, or 2% or more, or 2.5% or more, or 3% or more of the ureacomposition. In certain embodiments, the lipophilic component is 8% orless, 7.5% or less, 7% or less, 7.5% or less, 6% or less, 5.5% or less,5% or less, or 4.5% or less, or 4% or less, or 3.5% or less of the ureacomposition. Where the lipophilic component comprises, as predominantcomponent(s), fatty acids or analogous alkyl amines, these predominatecomponents can be 1% or more, or 1.5% or more, or 2% or more, or 2.5% ormore, or 3% or more of the urea composition; and 5% or less, or 4.5% orless, or 4% or less, or 3.5% or less of the urea composition.

An emollient, if present, can be a silicone oil such aspolydimethylsiloxane (i.e., dimethicone), petrolatum, or the like. Incertain embodiments, the emollient(s) are 0.5% or more, or 0.6% or more,or 0.7% or more, or 0.8% or more, or 0.9% or more, or 1% or more of theurea composition. In certain embodiments, the emollient(s) are 2% orless, or 1.9% or less, or 1.8% or less, or 1.7% or less, or 1.6% orless, or 1.5% or less, or 1.4% or less, or 1.3% or less, or 1.2% orless, or 1.1% or less, or 1% or less of the urea composition.

A non-greasy feel is measured in reference to oil-based ointments and bycomparison of the feel of the Example composition (described in theExample below), applied to skin at 1 mg/cm², compared to the oil-basedproduct described in the Table at Column 3 of U.S. Pat. No. 5,919,470(Bradley Pharmaceuticals, Inc.), applied in the same amount. While thefeel of compositions of the invention may vary, in making the comparisonbetween the non-greasy standard, the greasy standard, and theprospective non-greasy composition, it will be apparent which categorythe prospective composition falls within. The non-greasy skin feel maybe moist and smooth feeling, but the difference in greasy feel relativeto the greasy comparative shall be clear.

The hydrophilic polymer(s) can be any non-toxic water soluble polymer(s)that (in the aggregate) stabilize foam and contribute to film formationon the skin. Examples include polyvinyl pyrrolidone, polyethyleneglycol, starch, water-soluble derivatives of starch, cellulose, methylcellulose, hydroxymethylcellulose, other water-soluble derivatives ofcellulose, carbomers, or the like. For polyvinyl pyrrolidone, forexample, useful average molecular weights include from 8,000 to 63,000,such as about 38,000. For all polymers used in the composition, the sizeshould be sufficient to limit penetration of the horny layer of theskin, if skin penetration is an issue for the given polymer.

In certain embodiments, hydrophilic polymer(s) are 0.2% or more, 0.3% ormore, 0.4% or more, 0.5% or more, or 0.6% or more, or 0.7% or more, or0.8% or more, or 0.9% or more, or 1% or more, or 1.5% or more of theurea composition. In certain embodiments, the hydrophilic polymer(s) are3% or less, 2.5% or less, 2% or less, 1.5% or less, or 1.4% or less, or1.3% or less, or 1.2% or less, or 1.1% or less, or 1% or less of theurea composition.

The composition can also contain a humectant, such as glycerol,propylene glycol, other polyols, polydextrose, lactic acid, or the like.In certain embodiments, humectant(s) are 0.5% or more, or 0.6% or more,or 0.7% or more, or 0.8% or more, or 0.9% or more, or 1% or more, or1.2% or more, or 1.4% or more, or 1.6% or more, or 1.8% or more, or 2%or more, or 2.5% or more, or 3% or more, or 3.5% or more, or 4% or moreof the urea composition. In certain embodiments, the humectant(s) are 7%or less, or 6.5% or less, or 6.0% or less, or 5.8% or less, or 5.6% orless, or 5.4% or less, or 5.2% or less, or 5% or less of the ureacomposition.

The frothing agent can be, for example, a non-ionic detergent such asPolysorbate 20, polyoxyethylene sorbitan fatty acid esters, sorbitolfatty acid esters, or the like. In certain embodiments, the frothingagent(s) are 0.3% or more, or 0.4% or more, or 0.5% or more, or 0.6% ormore, or 0.7% or more, or 0.8% or more, or 0.9% or more, or 1% or more,or 1.1% or more, or 1.2% or more, or 1.3% or more, or 1.4% or more, or1.5% or more, or 1.6% or more, or 1.7% or more, or 1.8% or more, or 1.9%or more, or 2.0% or more, or 2.1% or more, or 2.2% or more, or 2.3% ormore of the urea composition. In certain embodiments, the frothingagent(s) are 4% or less, 3.5% or less, 3% or less, 2.9% or less, 2.8% orless, 2.7% or less, 2.6% or less, 2.5% or less, 2.4% or less, 2.3% orless, 2.2% or less, 2.1% or less, 2% or less, 1.9% or less, 1.8% orless, 1.7% or less, 1.6% or less, 1.5% or less, or 1.4% or less, or 1.3%or less, or 1.2% or less, or 1.1% or less, or 1% or less, or 0.9% orless, or 1.8% or less of the urea composition.

In certain embodiments, the urea composition can contain soothingagent(s) such as homogenized oatmeal. In certain embodiments, thesoothing agent(s) are 0.02% or more, 0.03% or more, 0.04% or more, 0.05%or more, or 0.06% or more, or 0.07% or more, or 0.08% or more, or 0.09%or more, or 0.01% or more of the urea composition. In certainembodiments, the soothing agent(s) are 0.2% or less, or 0.15% or less,or 0.14% or less, or 0.13% or less, or 0.12% or less, or 0.11% or less,or 1% or less of the urea composition.

Additional optional ingredients include sunscreens, antimicrobial agentsor preservatives, fragrances, and the like.

Suitable propellants include, for example, propane, butane, isobutene,other hydrocarbons, hydrofluorocarbons, chlorofluorocarbons(Cl/F/(H)/C), and the like.

The amount of urea composition applied to an affected area of skin canvary with a number of variables including the condition of the skin, thesensitivity of the patient or the area of skin, and the like. In anysingle administration, the delivery device can deliver to the affectedarea an appropriate layer of foam that provides an appropriate amount ofurea composition. The aerosol-driven foam can be applied to the affectedarea and rubbed into the skin until absorbed. Typically, the compositionis applied twice a day.

Topically applied urea is believed to dissolve the intercellular matrixof the skin which results in enhanced shedding of scaly, dry skin andthus a softening of the hyperkeratotic areas of the skin. Urea topicallyapplied to the nail plate has a similar effect on the intercellularmatrix of the nail plate. Topically applied urea can be used forenzymatic debridement and promotion of normal healing of surfacelesions, particularly where healing is retarded by local infection,necrotic tissue, fibrinous or purulent debris, or eschar. Topicallyapplied urea is useful for the treatment of hyperkeratotic conditionssuch as dermatitis (e.g., atopic dermatitis), psoriasis, xerosis,ichthyosis, eczema, keratosis, keratoderma, dry, rough skin, corns andcalluses, damaged, ingrown and devitalized nails, and the like.

EXAMPLES Example 1

The following composition is formulated:

Component Wt. % Water 46.47 PVP 0.95 Oatmeal 0.1 Stearic acid 3.13Propylene Glycol 2.9 Glycerin 2.0 Dimethicone 1.0 Phenonipe ™ (a mixtureof 0.5 preservatives from _) Triethanol amine 0.65 Polysorbate 20 2.30Urea 40.0 Total 100.00

The oatmeal is homogenized in a portion of the water. The remainingwater is heated to 70° C. With stirring, the following were added inorder: PVP, oatmeal slurry, and stearic acid. Then, the remainder isadded less the urea. The temperature controller is set to 60° C.,allowing the temperature to decline. When the temperature is down to 60°C., the urea is added in portions as follows: 8 parts of 100, 8 parts, 8parts, 16 parts, 16 parts, 16 parts, remainder. Care is taken that thetemperature is 60° C. or higher on each addition. The regulator is thenset to 25° C., and the composition is agitated for 30 minutes. Aerosoldispensers can be filled with the composition at 25° C.

Or, The water is heated to 70° C. With stiffing, the following wereadded in order: oatmeal, PVP, and stearic acid. Then, the remainder isadded less the urea. The temperature controller is set to 60° C.,allowing the temperature to decline. When the temperature is down to 60°C., the urea is added in portions as follows: 8 parts of 100, 8 parts, 8parts, 16 parts, 16 parts, 16 parts, remainder. Care is taken that thetemperature is 60° C. or higher on each addition. After the last ureaaddition, and after the temperature has again reached 60° C., theregulator is then set to 25° C., and the composition is agitated for 30minutes. Aerosol dispensers can be filled with the composition at 25°C., and with stiffing during filling.

Example 2

The following composition is formulated:

Component Wt. % Water 48.07 PVP 0.95 Oatmeal 0.1 Stearic acid 3.13Propylene Glycol 2.9 Glycerin 2.0 Dimethicone 1.0 Phenonipe ™ (a mixtureof 0.5 preservatives from _) Triethanol amine 0.65 Polysorbate 20 0.70Urea 40.0 Total 100.00

The oatmeal is homogenized in a portion of the water. The remainingwater is heated to 70° C. With stirring, the following were added inorder: PVP, oatmeal slurry, and stearic acid. Then, the remainder isadded less the urea. The temperature controller is set to 40° C.,allowing the temperature to decline. When the temperature is down to 50°C., the urea is added in portions as follows: 8 parts of 100, 8 parts, 8parts, 16 parts, 16 parts, 16 parts, remainder. Care is taken that thetemperature is 40° C. or higher on each addition. The regulator is thenset to 25° C., and the composition is agitated for 30 minutes. Aerosoldispensers can be filled with the composition at 25° C.

Or, The water is heated to 70° C. With stiffing, the following wereadded in order: oatmeal, PVP, and stearic acid. Then, the remainder isadded less the urea. The temperature controller is set to 40° C.,allowing the temperature to decline. When the temperature is down to 50°C., the urea is added in portions as follows: 8 parts of 100, 8 parts, 8parts, 16 parts, 16 parts, 16 parts, remainder. Care is taken that thetemperature is 40° C. or higher on each addition. After the last ureaaddition, and after the temperature has again reached 40° C., theregulator is then set to 25° C., and the composition is agitated for 30minutes. Aerosol dispensers can be filled with the composition at 25°C., and with stiffing during filling.

Definitions

The following terms shall have, for the purposes of this application,the respective meanings set forth below.

Effective Amount

To treat the indications of the invention, an effective amount of a ureawill be recognized by clinicians but includes an amount effective totreat, reduce, alleviate, ameliorate, eliminate or prevent one or moresymptoms of the disease sought to be treated or the condition sought tobe avoided or treated, or to otherwise produce a clinically recognizablefavorable change in the pathology of the disease or condition. Ineffective amount can be a dermatological treatment effectiveconcentration of urea.

Publications and references, including but not limited to patents andpatent applications, cited in this specification are herein incorporatedby reference in their entirety in the entire portion cited as if eachindividual publication or reference were specifically and individuallyindicated to be incorporated by reference herein as being fully setforth. Any patent application to which this application claims priorityis also incorporated by reference herein in the manner described abovefor publications and references.

While this invention has been described with an emphasis upon preferredembodiments, it will be obvious to those of ordinary skill in the artthat variations in the preferred devices and methods may be used andthat it is intended that the invention may be practiced otherwise thanas specifically described herein. Accordingly, this invention includesall modifications encompassed within the spirit and scope of theinvention as defined by the claims that follow.

What is claimed:
 1. A non-greasy, water-based foamable urea compositioncomprising: (a) urea 20-50% by weight; (b) one or more carboxylic acidcontaining lipophilic components; and (c) a titrant in an amount suchthat at least a portion of the one or more carboxylic acid containinglipophilic components are in ionized form.
 2. The non-greasy,water-based foamable urea composition of claim 1, wherein the one ormore carboxylic acid containing lipophilic components comprises a fattyacid.
 3. The non-greasy, water-based foamble urea composition of claim1, wherein the titrant is triethanolamine.
 4. The non-greasy,water-based foamable urea composition of claim 2, wherein the fatty acidis present in an amount of from 1-5% by weight.
 5. The non-greasy,water-based foamable urea composition of claim 1, further comprising afrothing agent.
 6. The non-greasy, water-based foamable urea compositionof claim 5, wherein the frothing agent is present in an amount of 0.3-4%by weight.
 7. The non-greasy, water-based foamable urea composition ofclaim 1, further comprising a humectant.
 8. The non-greasy, water-basedfoamable urea composition of claim 7, wherein the humectant is presentin an amount of from 0.5-7% by weight.
 9. The non-greasy, water-basedfoamable urea composition of claim 7, wherein the humectant is selectedfrom glycerol, propylene glycol, other polyols, polydextrose, lacticacid.
 10. The non-greasy, water-based foamable urea composition of claim7, comprising urea 40% by weight, povidone, propylene glycol, glycerin,dimethicone, triethanolamine, polysorbate 20, phenoxyethanol, parabens,homogenized oatmeal, and water.
 11. The non-greasy, water-based foamableurea composition of claim 7, comprising urea 35% by weight, povidone,propylene glycol, glycerin, dimethicone, triethanolamine, polysorbate20, phenoxyethanol, parabens, lactic acid, and water.
 12. Thenon-greasy, water-based foamable urea composition of claim 1, furthercomprising a soothing agent.
 13. The non-greasy, water-based foamableurea composition of claim 12, wherein the soothing agent is present inan amount of from 0.02-0.2% by weight.
 14. The non-greasy, water-basedfoamable urea composition of claim 12, wherein the soothing agentcomprises homogenized oatmeal.
 15. The non-greasy, water-based foamableurea composition of claim 1, further comprising an emollient.
 16. Thenon-greasy, water-based foamable urea composition of claim 15, whereinthe emollient is present in an amount of from 0.5-2% by weight.
 17. Thenon-greasy, water-based foamable urea composition of claim 1, furthercomprising one or more hydrophilic polymers.
 18. The non-greasy,water-based foamable urea composition of claim 17, wherein the one ormore hydrophilic polymers are present in an amount of from 0.5-1.5% byweight.
 19. The non-greasy, water-based foamable urea composition ofclaim 17, wherein the one or more hydrophilic polymers are selected frompolyvinyl pyrrolidone, polyethylene glycol, starch, cellulose, methylcellulose, hydroxymethyl celluslose, other water-soluble derivatives ofcellulose, water soluble derivatives of starch, or carbomers.
 20. Thenon-greasy, water-based foamable composition of claim 17, wherein theone or more carboxylic acid containing lipophilic components is stearicacid.
 21. The non-greasy, water-based foamable urea composition of claim1, further comprising a propellant.
 22. The non-greasy, water-basedfoamable urea composition of claim 20, wherein in the propellant isselected from propane, butane, isobutene, other hydrocarbons,hydrofluorocarbons, chlorofluorocarbons.
 23. An aerosol delivery devicecomprising the composition of claim 1 and a propellant.
 24. A method oftreating one or more indications of dermatitis, psoriasis, zerosis,ichthyosis, ecezema, keratosis, keratoderma, dry and rough skin, corns,calluses, damaged or ingrown and devitalized nails comprising applyingthe composition of claim 1 to the skin of a patient in need thereof.